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Abstract

Spinal muscular atrophy (SMA) is a devastating childhood motor neuron disease. SMA is caused by mutations in the survival motor neuron gene (SMN1), leading to reduced levels of SMN protein in the CNS. The actin-binding protein plastin 3 (PLS3) has been reported as a modifier for SMA, making it a potential therapeutic target. Here, we show reduced levels of PLS3 protein in the brain and spinal cord of a mouse model of SMA. Our study also revealed that lentiviral-mediated PLS3 expression restored axonal length in cultured Smn-deficient motor neurons. Delivery of adeno-associated virus serotype 9 (AAV9) harboring Pls3 cDNA via cisterna magna in SMNΔ7 mice, a widely used animal model of SMA, led to high neuronal transduction efficiency. PLS3 treatment allowed a small but significant increase of lifespan by 42%. Although there was no improvement of phenotype, this study has demonstrated the potential use of Pls3 as a target for gene therapy, possibly in combination with other disease modifiers.

Item Type:	Article
Authors/Creators:	Alrafiah, A and Karyka, E and Coldicott, I and Iremonger, K and Lewis, KE and Ning, K and Azzouz, M
Keywords:	spinal muscular atrophy, plastin 3, gene therapy
Journal or Publication Title:	Molecular Therapy - Methods & Clinical Development
Publisher:	Elsevier BV
ISSN:	2329-0501
DOI / ID Number:	10.1016/j.omtm.2018.01.007
Copyright Information:	Copyright 2018 The Author(s). Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) http://creativecommons.org/licenses/by-nc-nd/4.0/
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